RT Journal Article
SR Electronic
A1 Bitman, Michal
A1 Vrzal, Radim
A1 Dvorak, Zdenek
A1 Pavek, Petr
T1 Valproate activates ERK signaling pathway in primary human hepatocytes
JF Biomedical papers
YR 2014
VO 158
IS 1
SP 039
OP 043
DO 10.5507/bp.2012.038
UL https://biomed.papers.upol.cz/artkey/bio-201401-0006.php
AB Aim: Valproic acid (VPA) is a widely-used anticonvulsant and mood-stabilizing agent. VPA is also known to inhibit histone deacetylases (HDACs) affecting the expression of numerous genes.
Methods: In the present study, we examined the effect of VPA on the extracellular signal-related kinase (ERK, p42/p44) pathway (Ras-Raf-MEK-ERK) belonging to the mitogen-activated protein kinases (MAPKs) pathways in primary human hepatocytes. In the liver, the pathway is associated with progression of hepatocellular carcinoma.
Results: We found that VPA in a therapeutically relevant concentration (500 µM) activates the ERK pathway, as indicated by increased ERK Thr202/Tyr204 phosphorylation. Interestingly, a prototype HDAC inhibitor, trichostatin A, also activated ERK phosphorylation in primary human hepatocytes. These data suggest that HDAC inhibition might be the primary stimulus for ERK pathway activation in primary human hepatocytes. Notably, U0126, a MEK1 inhibitor, was ineffective in inhibiting ERK pathway activation, likely due to its metabolic deactivation in metabolically competent primary human hepatocytes.
Conclusion: We conclude that VPA activates the ERK pathway in primary human hepatocytes.